de Aquino Sibele Nascimento, Hoshi Ryuichi, Bagordakis Elizabete, Pucciarelli Maria Giulia Rezende, Messetti Ana Camila, Moreira Helenara, Bufalino Andreia, Borges Andréa, Rangel Ana Lucia, Brito Luciano Abreu, Oliveira Swerts Mario Sergio, Martelli-Junior Hercilio, Line Sergio R, Graner Edgard, Reis Sílvia R A, Passos-Bueno Maria Rita, Coletta Ricardo D
Department of Oral Diagnosis, School of Dentistry, State University of Campinas, Piracicaba, São Paulo, Brazil.
Birth Defects Res A Clin Mol Teratol. 2014 Jan;100(1):30-5. doi: 10.1002/bdra.23199. Epub 2013 Nov 19.
Polymorphisms within the MTHFR (rs2274976) and MTHFD1 (rs2236225) genes were previously associated with maternal susceptibility for having an offspring with nonsyndromic cleft lip with or without cleft palate (NSCL/P) in the Brazilian population. However, as the genotypes of the patients with NSCL/P were not evaluated, it is not clear whether the effects are associated with maternal or offspring genotypes. The aim of this study was to evaluate the association of rs2274976 and rs2236225 in the pathogenesis of NSCL/P.
By using the TaqMan 5'-exonuclease allelic discrimination assay, the present study genotyped the rs2274976 and rs2236225 polymorphisms in 147 case-parent trios, 181 isolated samples of NSCL/P and 478 healthy controls of the Brazilian population. Transmission disequilibrium test and structured case-control analysis based on the individual ancestry proportions were performed.
The transmission disequilibrium test showed a significant overtransmission of the rs2274976 A allele (p = 0.004), but no preferential parent-of-origin transmission was detected. The structured case-control analysis supported those findings, revealing that the minor A allele of rs2274976 was significantly more frequent in NSCL/P group compared with control group (p = 0.001), yielding an odds ratio of 3.46 (95% confidence interval, 2.05-5.85). No association of rs2236225 polymorphism with NSCL/P was observed in both transmission disequilibrium test and case-control analysis.
The results of the study revealed that the presence of the rs2274976 A allele is a risk marker for the development of NSCL/P in the Brazilian population.
MTHFR（rs2274976）和MTHFD1（rs2236225）基因内的多态性先前在巴西人群中与母亲生育非综合征性唇裂伴或不伴腭裂（NSCL/P）后代的易感性相关。然而，由于未评估NSCL/P患者的基因型，尚不清楚这些影响是与母亲还是后代的基因型相关。本研究的目的是评估rs2274976和rs2236225在NSCL/P发病机制中的关联。
本研究采用TaqMan 5'-外切核酸酶等位基因鉴别分析方法，对147例病例-亲代三联体、181例NSCL/P独立样本和478例巴西人群健康对照中的rs2274976和rs2236225多态性进行基因分型。进行了传递不平衡检验和基于个体祖先比例的结构化病例对照分析。
传递不平衡检验显示rs2274976 A等位基因存在显著过度传递（p = 0.004），但未检测到优先的亲源传递。结构化病例对照分析支持了这些发现，表明与对照组相比，rs2274976的次要A等位基因在NSCL/P组中显著更常见（p = 0.001），优势比为3.46（95%置信区间，2.05 - 5.85）。在传递不平衡检验和病例对照分析中均未观察到rs2236225多态性与NSCL/P的关联。
研究结果表明，rs2274976 A等位基因的存在是巴西人群中NSCL/P发生的风险标志物。
